1. Field of Invention
This invention relates generally to medical foods and dietary supplements that augment neurotransmitter production by simultaneous administration of oral neurotransmitter precursors, a precursor uptake stimulator, a neurotransmitter releaser, a disinhibitor of the adenosine neuron brake, and an activator of adenylate cyclase to prevent tachyphylaxis.
2. Description of Prior Art
There has been increasing attention to the role that neurotransmitters and neuromodulators play in various aspects of health and disease(Growdon and Wurtman, 1979; Growdon and Wurtman, 1980; Wurtman, 1987b; Wurtman, 1987a; Wurtman, 1988; Wurtman and Fernstrom, 1976; Wurtman and Growdon, 1978). Neurotransmitters are the chemical messengers that allow one neuron to communicate with either a second neuron or an effector organ. The classic neurotransmitters are acetylcholine and norepinephrine that function within the autonomic nervous system. The autonomic nervous system, operating through its neurotransmitters, controls important body functions, such as heart rate, respiratory rate, gastrointestinal function, appetite, sleep, sexual performance, blood pressure and mood.
The increased scrutiny has lead to an appreciation of the effects that neurotransmitters and neuromodulators have on derangements of cognitive function, sleep disorders, mood, and memory. It is also known that neurotransmitters and neuromodulators play a crucial role in regulating the function of the cardiovascular, reproductive, musculoskeletal, immune, respiratory, and memory systems(Amenta et al., 1991;Arai and Iizuka, 1988,Beal et al., 1988;Bruno et al., 1995;Doraiswamy et al., 1991;Dumka et al., 1998;Gottfries, 1996;Nakamura et al., 1988;Nazarali and Reynolds, 1992;Perry, 1991;Tomkins and Sellers, 2001;Wurtman and Zervas, 1974).
Numerous pharmaceutical agents have been developed which exert their effects by interfering with one or more neurotransmitter or neuromodulator systems. An important pharmaceutical mechanism is that of reuptake inhibition of neurotransmitters in the synaptic cleft of neuron junctions(2001;Burke et al., 2002;Fava and Rankin, 2002; Olver et al., 2001;Spillmann et al., 2001;Stewart, 1998). The pharmaceuticals fluoxetine and fenfluramine are examples of neurotransmitter reuptake inhibitors.
All known neurotransmitters are synthesized within the neurons from their requisite precursor molecules. Thus, tryptophan becomes serotonin, choline becomes acetylcholine, tyrosine becomes epinephrine, and arginine becomes nitric oxide. The precursors are generally amino acids and are produced in the liver or are derived from the diet.
Importantly, administration of neurotransmitter and neuromodulator precursors has long been known to induce a physiologic response when initially administered. For example, administration of tryptophan-the precursor to the neurotransmitter serotonin, leads to the production of serotonin(Fernstrom et al., 1977;Fernstrom and Wurtman, 1971;Fernstrom and Wurtman, 1997;Growdon and Wurtman, 1980;Lehnert and Wurtman, 1993;Lieberman et al., 1985;Wurtman, 1982;Wurtman, 1984;Wurtman, 1987a;Wurtman and Fernstrom, 1974;Wurtman and Growdon, 1978). Administration of choline leads to the production of acetylcholine(Blusztajn and Wurtman, 1983;Cohen and Wurtman, 1975;Cohen and Wurtman, 1976;Millington and Wurtman, 1982;Wurtman, 1991).
Although, the administration of neurotransmitter precursors is known to acutely produce neurotransmitters, as evidenced by a physiologic response, the physiologic response induced by administration of a precursor to a neurotransmitter is often inconsistent, weak in magnitude, and rapidly attenuates so that the precursor administration is largely ineffective. The physiologic loss of neurotransmitter function often results in abnormal physiology and human disease. Accordingly, there is a need for an effective means for promoting the production of neurotransmitters and neuromodulators by administration of precursors, while avoiding the attenuation that frequently occurs with such precursor administration.
One approach to producing neurotransmitter and neuromodulators by the administration of precursors to the neurotransmitter was introduced by Wurtman and associates. They used tryptophan as a precursor to serotonin. Serotonin is known to reduce craving for carbohydrates. In Wurtman, et al, U.S. Pat. No. 4,210,637, a composition and method for selectively suppressing appetite for carbohydrates is described. The method includes administration of the serotonin precursor, tryptophan, along with a carbohydrate in order to suppress craving for carbohydrate.
Wurtman subsequently administered tryptophan to humans in doses up to 2300 mg per day for many days but did not find a consistent appetite suppression because many of the subjects experienced attenuation of the response secondary to tolerance. Wurtman, et al, in U.S. Pat. No. 4,309,445, abandoned the use of precursor administration to increase serotonin production and described a method that focused on the use of a serotonin reuptake inhibitor, d-fenfluramine, to increase brain levels of serotonin, thereby reducing craving for carbohydrates. The d-fenfluramine and a related molecule, fenfluramine, were subsequently administered to several million humans, a practice discontinued because the re-uptake inhibition caused side effects, including heart valve lesions and pulmonary hypertension.
In U.S. Pat. No. 4,687,763, Wurtman, et al, disclosed that tryptophan feeding in conjunction with melatonin can acutely increase brain serotonin concentration and reduce carbohydrate craving. They did not examine attenuation or tolerance in this disclosure. They did disclose, however, that on initial administration of tryptophan, serotonin concentration in the brain increases.
In Pollack, U.S. Pat. No. 4,650,789, a method and composition for increasing production of serotonin is described. The method requires that tryptophan be concomitantly administered with acetylsalicylic acid. They only disclosed acute administration of the precursor and did not disclose either the tolerance or attenuation of precursor administration. They did not suggest a solution for the attenuation problem.
In 1992, Weintraub observed that phentermine and fenfluramine when used together induced weight loss, reduced appetite and reduced carbohydrate craving in humans. The results of using phentermine and fenfluramine were attributed to their separate effects on serotonin and dopamine. Weight loss could be obtained for approximately 3 months, but the effects attenuated, and a weight plateau was reached. The patients could only sustain their initial weight loss, but not lose additional weight by maintaining the use of the drugs, or actually increasing the dose of the drugs. The phentermine/fenfluramine combination had induced a physiologic tolerance. If the patients discontinued the drugs, rebound weight gain occurred, frequently returning the patients to their original weight. In many patients, super-rebound occurred inducing a weight gain that exceeded the original weight loss. Thus, the initial physiologic tolerance caused a deleterious side effect of rebound and super-rebound.
In Wurtman, et al, U.S. Pat. No. 5,118,670, a composition and method for increasing brain dopamine is described. The effects described are acute effects. The combination is not administered for sufficient duration to assess attenuation and tolerance. Similarly, in Wurtman, et al, U.S. Pat. No. 4,673,689, a method is disclosed for the use of tyrosine to potentiate sympathomimetic agents such as phenyipropanolamine, ephedrine, and pseudoephedrine. The effects described are acute and tolerance is not assessed. The combination of tyrosine with the sympathomimetic agents has not been commercially applied, suggesting that attenuation is an important factor. Such tolerance to sympathomimetic agents is a well known effect of the use of sympathomimetic agents. Tolerance is described in the standard texts of pharmacology, where loss of response after successive administration of sympathomimetic agents is used to teach the general principals of physiologic tolerance and dependence.
Wurtman (U.S. Pat. No. 4,636,494) disclosed the administration of choline co- administered with a drug to augment brain production of acetylcholine. They showed inconsistent results with an approximately 50% response rate. They administered the choline for two weeks and did not document attenuation
Delgado, et al demonstrated that ingestion of tryptophan free diets in patients with depression results in a rapid decline of blood plasma concentrations of tryptophan. The reduction of blood tryptophan resulted in rapid onset of symptoms of depression.
Richardson (U.S. Pat. No. 5,919,823) using the administration of large neutral amino acids found that movement disorders secondary to drugs could be treated but that the response is often inconsistent and improvement was only seen in approximately 50% of patients and for short periods.
Hinz (U.S. Pat. No. 6,403,657) disclosed the simultaneous administration of a serotonin reuptake inhibitor with a monoamine oxidase inhibitor along with supplementation with 5-hydroxytryptophan and tyrosine to ameliorate the plateau phase of weight loss. They disclosed the use of Citalopram and phentermine with tyrosine. In U.S. Pat. No. 6,384,008, Hinz disclosed the use of phentermine and Citalopram with both tyrosine and 5-hydroxytryptophan.
These observations all indicate that administration of a neurotransmitter precursor results in production of the associated neurotransmitter. The production of the neurotransmitter results in a physiologic response. The response to the precursor is short-lived and inconsistent. Administration of precursor to neurotransmitters may ameliorate some aspects of tachyphylaxis.
These observations indicate that there is a need for improved methods to stimulate neurotransmitter production. These methods should lead to augmented and sustained response while avoiding tachyphylaxis to precursor administration.
The pharmacology literature has long recognized the existence of tolerance and attenuation, also termed tachyphylaxis. The effect is particularly prominent in psychotropic agents including amphetamines, analgesics, antidepressants, anti-anxiety agents, and psycho stimulants such as cocaine. The mechanisms related to tolerance are obscure but are thought to be related to upregulation of receptors and upregulation of enzyme systems related to first messenger receptor systems. Despite extensive study, avoidance of tolerance has been an elusive goal.
For example, attenuation to nitroglycerin has been particularly well studied. Continuous administration of nitroglycerin by either oral or transcutaneous routes leads to both attenuation and complete tolerance to nitroglycerin. The attenuation occurs over 7 to 10 days of administration. Withdrawal of the agents leads to a nitrate withdrawal syndrome. Despite extensive study, avoidance of nitrate tolerance has not been achieved. The effects of nitroglyerin are related to nitric oxide metabolism.
Shell has observed in studies dating to 1987 that the initial effects of formulations containing neurotransmitter precursors rapidly attenuate. Appetite suppression from tyrosine acutely occurs but is lost in approximately 7 days. Choline administered in combination with xanthines induces heart rate reduction and altered heart rate variability but the combination attenuated in approximately 7 days. These observations are consistent with the known effects of xanthines, which show attenuation within 7 days of administration. Caffeine attenuation effects are also well known, particularly the alteration of heart rate and leads to coffee withdrawal syndromes. The attenuation of theophylline in the treatment of asthma is well documented, leading to its reduced use in the treatment of asthma.
Administration of amino acid precursors to stimulate neurotransmitter activity depends on an active uptake of the amino acid into the neuron, synthesis of the neurotransmitter and release of the neurotransmitter by the neuron. Agents that can increase uptake of amino acids into neurons synthesis into include plant substances that contain flavanoids (Fitzpatrick), herbs such as ginkgo biloba, spices such as cinnamon, certain amino acids such as glutamine and histadine, xanthines such as caffeine and certain vitamins. Ginkgo biloba for example is known to increase the synthesis of acetyl choline from choline by increasing the uptake of choline(Klein et al., 1997;Kristofikova and Klaschka, 1997;Nathan, 2000). Cinnamon is known to increase the uptake of arginine to enhance the synthesis of nitric oxide. Caffeine is known to increase the production of norepinephrine from tyrosine(Lieberman and Wurtman, 1986;Park et al., 1999).
Agents that are known to cause release of neurotransmitters from neurons include the stimulatory amino acids glutamate and aspartate(Krebs, 1992;Ruzicka and Jhamandas, 1993). In addition, agents that can stimulate release of neurotransmitters include both the xanthines and the sympatheticomimetic agents(Lieberman and Wurtman, 1986;White et al., 1997). The xanthines include theobromine and caffeine. The sympatheticomimetic agents include ephedrine.
Many cell, particularly neurons, are inhibited from activity by active cell mechanisms. The receptors that control the active inhibition of neurons are the purinoreceptors. These receptors respond to adenosine containing molecules including ATP, ADP, AMP, and adenosine. This inhibitory effect of adenine containing molecules on neuron function has been termed the adenosine brake. In neurons, the adenosine brake acts to inhibit a neuron from firing. Thus, provision of an amino acid precursor such as tyrosine, to a non-firing neuron will result in no response, the tyrosine will be cleared from the blood, and no physiologic effect will be noted. Thus, to enhance the effectiveness of amino acid precursors to the neurotransmitters, a means must be found to relieve the adenosine brake. Inhibitors of the adenosine brake include the xanthines. Caffeine is an especially potent inhibitor of the adenosine brake. For example, Dullo, et al., demonstrated that in brown adipose tissue caffeine increased fat cell oxygen consumption and the increase is directly related to the ability of caffeine to relieve the adenosine brake.
Attenuation and tolerance limit the utility of administration of amino acid precursors to the neurotransmitters. Tolerance is particularly prevalent in the sympatheticomimetic agents-those that stimulate cyclic AMP production by activation of adenyl cyclase. These agents stimulate cyclic AMP and appear to down regulate the number of receptor molecules to account for the observed attenuation and tolerance. Activators of adenyl cyclase that do not down regulate the adenyl cyclase receptors could have potential utility in avoiding attenuation and tolerance. A class of agents that stimulates adenyl cyclase without attenuation includes the herbs Hawthorn Berry and Willow Bark. Hawthorn Berry can be used for many months to stimulate heart contractility without attenuation while activating adenyl cyclase. The use of Hawthorn Berry with amino acid precursors to stimulate neurotransmitters without attenuation has not been used prior to our invention.
Xanthines are a class of agents that have similar but not identical effects. The xanthines include ephedrine, caffeine, and theobromine. The potency of the xanthines has generally been ranked according to the ephedrine, caffeine, and theobromine series. The effects of the individual xanthines are not identical. Caffeine is a potent stimulant to uptake and release of amino acids while ephedrine is a potent stimulant to heart rate. Moreover, the xanthines are often used in combination with sympatheticomimetic agents-ephedrine with caffeine is a frequent combination.
A large number of dietary supplements and medical foods have used various combination of these mechanism with variable effects. For example, ephedrine and caffeine have been combined. Tyrosine, ephedrine, and caffeine have been combined in various proportions. Choline and ginkgo biloba have been combined. The combination of a precursor, stimulant to uptake/release, inhibition of the adenosine brake, and non- attenuating activation of adenyl cyclase has not been utilized prior to this invention.
In experiments dating to 1987, the inventors have worked on combinations of these mechanisms that have produced results that are both synergistic and surprising. The results indicate that the combination of the five elements lead to a result that is more then the individual agents acting alone. The effects are sustained and do not attenuate.
The methods used to assess the production of neurotransmitters include various tests of physiologic function. The tests include but are not limited to test of heart rate, tests of heart rate variability, tests of cardiac repolarization, tests of body temperature, tests of symptoms reflecting autonomic nervous system function and tests of blood flow.
Neurotransmitter synthesis, release, and reuptake provide the chemical messengers used to control the autonomic nervous system. Therefore, physiologic tests of autonomic function reflect the production of neurotransmitters.
For example, it is long known that heart rate is under the control of the autonomic nervous system. The human autonomic nervous system controls the heart rate on a beat to beat basis to control the amount of blood ejected by the heart. The balance between the sympathetic and parasympathetic components of the autonomic nervous system will determine the cycle length of heart beat. Beat-to-beat heart rates and average heart rates are controlled by the autonomic nervous systems. The heart rate and changes in heart rate can be used to assess the status of neurotransmitter production.
A more sophisticated measurement of autonomic nervous system control of heart rate is termed heart rate variability (HRV) analysis. In this method at least five minutes of heart rate data is accumulated. The data is then analyzed in either the time domain or the frequency domain. In the time domain, each successive beat is calculated as an RR- interval in msec. A series of statistics are calculated including means and variances to reflect the autonomic control of heart rate.
In the frequency domain methods, the successive RR-intervals are converted to frequency using Fast Fourier Transform or similar methods. Using the derived frequencies several bands are identified including the very low frequency (VLF), the low frequency (LF), and the high frequency (HF). The sum of all the bands is termed the total power. The area of the HF band has been identified with parasympathetic autonomic nervous system function. The LF/HF ratio is identified with Sympathetic/parasympathetic balance. There is no specific marker yet identified that is specific for sympathetic autonomic nervous system function. The total power is a measure of the total activity of the autonomic nervous system-reduced total power reflects suppression of autonomic nervous system activity.
Another measure of autonomic nervous system activity is a measurement of the QTc-interval on the electrocardiogram. Prolongation of the QTc-interval is a reflection of enhanced sympathetic activity.
The assessment by physiologic tests such as change in heart rate, change in heart rate variability, change in the QTc-interval, change in body temperature, and change in symptoms reflective of autonomic function can be used to measure the activity of the autonomic nervous system and thus a measure of neurotransmitter production.
Accordingly, this invention describes a method to stimulate augmented neurotransmitter synthesis, providing sustained neurotransmitter activity, while avoiding attenuation of precursor administration.